We have shown that the rabbit disc degeneration model, which is induced by puncturing the annulus fibrosus with needles of defined gauges, resulted in reproducible, degenerative changes that could be quantitatively assessed. Our initial hypothesis that an injection of the growth factor, osteogenic protein-1, is able to regenerate the intervertebral disc was shown to be true using this model. This promising protein injection therapy approach will soon be translated into a Phase I clinical trial as the first injection therapy using a growth factor. The approaches in the proposed funding period are to: (1) test if the injection of a growth factor into a disc also stimulates repair in a more clinically relevant model using adult rabbits;(2) expand therapeutic approaches to the application of cytokine inhibitory molecules;and (3) delineate the limitations of such therapy under conditions where nutrition levels in the disc are compromised. In addition, efforts will be extended to identify changes in nerve-related cytokines, i.e. nerve growth factor, in the rabbit model and in cadaveric samples, as potential surrogate markers of low back pain. Hypothesis 1: Disc degeneration can be delayed or reversed by manipulating the balance between anabolic and catabolic pathways;some manipulations will result in decreased pain associated with disc degeneration. In Specific Aim 1, we will test if growth factors (osteogenic protein-1, growth differentiation factor-5) and/or inhibitory molecules of cytokines (interleukin-1 receptor antagonist, tumor necrosis factor-a soluble receptor) delay the progression of disc degeneration or restore the degenerated disc using an in vivo protein injection in a mature rabbit chronic disc degeneration model. Hypothesis 2: Compromised nutrient transport through the endplate limits cell-mediated disc repair induced by the application of a growth factor. In Specific Aim 2 we will investigate changes in nutrient transport in the rabbit annular puncture model of disc degeneration and identify the presence of a critical level of nutrient transport that is deleterious to matrix metabolism. Low back pain is responsible for enormous human suffering, high health care costs and significant socioeconomic losses. Although the etiology of back pain is often unknown, the intervertebral disc is a significant source of back problems. The results from this study will advance the field of biological treatment for intervertebral disc degeneration.